TCGA mRNA Expression Analysis of the Heme Biosynthesis Pathway in Diffusely Infiltrating Gliomas: A Comparison of Typically 5-ALA Fluorescent and Non-Fluorescent Gliomas.

Mario Mischkulnig,Daniela Lötsch,Florian J Jaklin,Petra A Mercea,Shawn Hervey-Jumper,Mitchel S Berger,Martin Borkovec,Barbara Kiesel,Lisa I Wadiura,Friedrich Erhart,Thomas Roetzer,Karl Roessler,Georg Widhalm

doi:10.3390/cancers12082043

Abstract

5-Aminolevulinic acid (5-ALA) is a fluorescent dye that after metabolization to Protoporphyrin IX (PpIX) by the heme biosynthesis pathway typically leads to visible fluorescence in WHO grade IV but not grade II gliomas. The exact mechanism for high PpIX levels in WHO grade IV gliomas and low PpIX levels in WHO grade II gliomas is not fully clarified. To detect relevant changes in mRNA expression, we performed an in-silico analysis of WHO grade II and IV glioma sequencing datasets provided by The Cancer Genome Atlas (TCGA) to investigate mRNA expression levels of relevant heme biosynthesis genes: Solute Carrier Family 15 Member 1 and 2 (SLC15A1 and SLC15A2), Aminolevulinate-Dehydratase (ALAD), Hydroxymethylbilane-Synthase (HMBS), Uroporphyrinogen-III-Synthase (UROS), Uroporphyrinogen-Decarboxylase (UROD), Coproporphyrinogen-Oxidase (CPOX), Protoporphyrinogen-Oxidase (PPOX), ATP-binding Cassette Subfamily B Member 6 (ABCB6)/G Member 2 (ABCG2) and Ferrochelatase (FECH). Altogether, 258 WHO grade II and 166 WHO grade IV samples were investigated. The mRNA expression levels showed significant differences in 8 of 11 examined genes between WHO grade II and IV gliomas. Significant differences in mRNA expression included increases of HMBS, UROD, FECH and PPOX as well as decreases of SLC15A2, ALAD, UROS and ABCB6 in WHO IV gliomas. Since the majority of changes was found in directions that might actually impair PpIX accumulation in WHO grade IV gliomas, additional studies are needed to analyze the corresponding factors of the heme biosynthesis also on protein level.

Highlights

Infiltrating gliomas (DIG) are the most common primary malignant tumors of the central nervous system (CNS) [1]
According to our search in the The Cancer Genome Atlas (TCGA) PANCAN database, we identified a total of 1131 specimens from Diffusely infiltrating gliomas (DIG).toOf these, data on expression was available in 695we specimens
Even though our study provides a comprehensive overview of mRNA expression data from a large number of WHO grade II and WHO grade IV gliomas, important limitations have to be considered: (1) Since no data on 5-Aminolevulinic acid (5-ALA) use and status are available in the TCGA dataset, we did not directly compare fluorescent vs. non-fluorescent samples but used WHO grade II vs. WHO grade IV as closely related surrogate subgroups

Summary

Introduction

Infiltrating gliomas (DIG) are the most common primary malignant tumors of the central nervous system (CNS) [1]. While each WHO grade shows specific histopathological features and prognosis, maximal safe resection is the initial therapy of choice in DIG independent of the WHO grade [2,3,4]. The extent of resection (EOR) was identified as a key factor for prognosis, precise identification of resection borders still remains challenging due to infiltrative growth of gliomas [5,6,7]. Innovative tools to support intraoperative guidance and detection of residual tumor tissue during surgery of DIG have been established over the past decades to maximize the EOR [8,9,10,11]. Aside from neuronavigation, ultrasound and intraoperative magnetic resonance imaging (MRI), fluorescence-guided surgery using

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